Antigenic variation

Abstract

The hallmark of an infection with Plasmodium falciparum is sequestration, the adherence of erythrocytes infected with asexual stage parasites to endothelial cells of blood vessels. Identification and characterization of the molecules expressed on the surface of parasite-infected erythrocytes, as well as of the endothelial receptors to which these proteins bind, have been an intense area of research. The infected erythrocyte displays on its surface high-molecular-weight antigens encoded by members of the var multigene family. Expression of these proteins correlates with cytoadherence and is involved in antigenic variation in malaria parasites. Since the cloning of the first var gene in 1995, much research has been aimed at understanding the regulation of var expression. Chen et al., 1998 Chen Q et al. Developmental selection of var gene expression in Plasmodium falciparum. Nature. 1998; 394: 392-395 Crossref PubMed Scopus (270) Google Scholar . have now described an interesting observation that suggests a mechanism of antigenic switching distinct from that observed in other pathogens. Using RT–PCR on a strain of P. falciparum with homogeneous adhesiveness (i.e. binding primarily one endothelial receptor), several distinct var mRNAs were detected. Analysis of individual cells by RT–PCR also revealed the presence of different var transcripts, suggesting that multiple var genes were being expressed in a single cell. To further characterize this expression, several cDNAs were cloned and used to hybridize to chromosomes separated by pulsed-field gel electrophoresis. In single parasites, var expression occurred from several chromosomes. Using monospecific sera raised against the DBL-1 domain of PfEMP-1, and human sera from immune individuals, only one PfEMP-1 was immunoprecipitated. This intriguing observation indicates that although several different var genes may be expressed within a single parasite, only one of the variants of PfEMP-1 is ultimately expressed. Thus, multiple var genes could be active early in intracellular development of the parasites, and switching to a single var gene would then occur as they mature. This post-transcriptional mechanism of var expression might occur through a selective or nonselective degradation of var mRNAs and would be a means of maintaining the adhesive phenotype and regulating the expression of antigens on the surface of the infected erythrocyte. Development of a nuclear run-on assay for P. falciparum to examine nascent var transcripts should allow this hypothesis to be tested.